Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels

ABSTRACT

Pharmaceutically acceptable hydrogel polymers of natural, recombinant or synthetic origin, or hybrids thereof, are introduced in a dry, less hydrated, or substantially deswollen state and rehydrate in a physiological environment to undergo a volumetric expansion and to affect sealing, plugging, or augmentation of tissue, defects in tissue, or of organs. The hydrogel polymers may deliver therapeutic entities by controlled release at the site. Methods to form useful devices from such polymers, and to implant the devices are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.:10/616,055, filed Jul. 9, 2003, entitled “Methods of Using In SituHydration of Hydrogel Articles for Sealing or Augmentation of Tissue orVessels” which is a continuation of U.S. application Ser. No.:09/134,199, filed on Aug. 14, 1998, entitled “Methods of Using In SituHydration of Hydrogel Articles for Sealing or Augmentation of Tissue orVessels”, the disclosures of which are herein incorporated by reference.

FIELD OF THE INVENTION

This invention relates to making and using medically useful articlesformed from hydrogels. More specifically, the present invention relatesto the methods of using in situ hydration of hydrogel articles to sealor augment tissues or organs.

BACKGROUND OF THE INVENTION

Hydrogels are materials that absorb solvents (such as water), undergorapid swelling without discernible dissolution, and maintainthree-dimensional networks capable of reversible deformation. See, e.g.,Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Pub.Co., Lancaster, Pa. (1993).

Hydrogels may be uncrosslinked or crosslinked. Uncrosslinked hydrogelsare able to absorb water but do not dissolve due to the presence ofhydrophobic and hydrophilic regions. A number of investigators haveexplored the concept of combining hydrophilic and hydrophobic polymericcomponents in block (Okano, et al., “Effect of hydrophilic andhydrophobic microdomains on mode of interaction between block polymerand blood platelets”, J. Biomed. Mat. Research, 15:393-402 (1981), orgraft copolymeric structures (Onishi, et al., in Contemporary Topics inPolymer Science, (Bailey & Tsuruta, Eds.), Plenum Pub. Co., New York,1984, p. 149), and blends (Shah, “Novel two-phase polymer system,”Polymer, 28:1212-1216 (1987) and U.S. Pat. No. 4,369,229 to Shah) toform the “hydrophobic-hydrophilic” domain systems, which are suited forthermoplastic processing. See, Shah, Chap. 30, in Water Soluble Polymers(Shalaby et al., Eds.), Vol. 467, ACS-Symp. Ser., Amer. Chem. Soc.,Washington (1991). These uncrosslinked materials can form hydrogels whenplaced in an aqueous environment.

Hydrogels may be formed by physical or chemical crosslinking, or acombination of these two processes. Physical crosslinking takes place asa result of ionic linkages, hydrogen bonding, Van der Waals forces, orother such physical forces. Chemical crosslinking occurs due to theformation of covalent linkages. Covalently crosslinked networks ofhydrophilic polymers, including water-soluble polymers are traditionallydenoted as hydrogels (or aquagels) in the hydrated state. Hydrogels havebeen prepared based on crosslinked polymeric chains ofmethoxypoly(ethylene glycol) monomethacrylate having variable lengths ofthe polyoxyethylene side chains, and their interaction with bloodcomponents has been studied (Nagaoka et al., in Polymers as Biomaterial(Shalaby et al., Eds.) Plenum Press, 1983, p. 381). A number of aqueoushydrogels have been used in various biomedical applications, such as,for example, soft contact lenses, wound management, and drug delivery.

The concept of injecting hydrogels to fill spaces or tracks is describedin U.S. Pat. No. 5,645,583 to Villain et al. That patent describes apolyethylene oxide gel implant that may be injected into a human bodyfor tissue replacement and augmentation. U.S. Pat. No. 5,090,955 toSimon describes the use of gels in ophthalmology for corneal tissueaugmentation procedures such as Gel Injection Adjustable Keratoplasty(GIAK). Neither patent mentions of augmentation of such tissue byhydration and swelling-induced shape changes in the tissue. Instead, forexample, the Simon patent describes “smoothing and massaging” of thecornea to remove excess hydrogel material.

Non-degradable hydrogels made from poly(vinyl pyrrolidone) andmethacrylate have been fashioned into fallopian tubal occluding devicesthat swell and occlude the lumen of the tube. See, Brundin, “Hydrogeltubal blocking device: P-Block”, in Female Transcervical Sterilization,(Zatuchini et al., Eds.) Harper Row, Philadelphia (1982), pp. 240-244.Because such hydrogels undergo a relatively small amount of swelling andare not absorbable, so that the sterilization is not reversible, thedevices described in the foregoing reference have found limited utility.

U.S. Pat. No. 5,324,775 to Rhee et al. describes injectable particlesbased on swellable natural polymers that may be suspended in anon-aqueous fluid, e.g., an oil. The particles are formed from groundsolid articles and may be injected into soft tissue to rehydrate in-situto augment the tissue. A significant drawback of the compositionsdescribed in that patent, however, is the requirement that a non-aqueousand water insoluble carrier be used to inject the particles.

In view of the foregoing, it would be desirable to provide methods ofusing hydrogel materials, for example, for temporary occlusion of a bodylumen or for tissue augmentation, that overcome the drawbacks ofpreviously known compositions and methods.

It therefore would be desirable to provide methods of forming and usingmedically useful articles that comprise absorbable hydrogels, capable ofundergoing a relatively large degree of swelling in-situ.

In addition to tissue augmentation and lumen occlusion, absorbablehydrogel articles may have application in sealing surgically createdvoids. For example, tissue biopsy is a very commonly performed minorsurgical procedure, and is often to confirm or rule out the presence ofdisease that has been identified by a previously undertaken diagnosticmodality, e.g., X-rays or ultrasound imaging.

Often needle biopsies are performed on solid organs using needles thatare introduced from the outside of the patient's body, across the pelvicor thoracic wall.

Visualization in performing such procedures is typically limited and thecutting action of the needle often generates associated complicationssubsequent to the biopsy. Increasing experience with percutaneous biopsyhas clarified some subtle points and controversies about possiblecomplications and their prevention.

For example, while hemorrhage is possible with even the smallestaspiration needle, the risk has generally been assumed to increasesignificantly with the use of larger cutting needles and/or in patientswith coagulation deficiencies. Some argue that the benefits attainedwith the use of cutting needles therefore is not worth the added risk.Unfortunately, while fine-needle aspiration techniques may provide thenecessary tissue for cytologic diagnosis in many cases, there aresituations in which cutting needles are needed for optimal diagnosticaccuracy, such as biopsy of the retroperitoneum (when lymphoma is likelyand must be typed) and in the diagnosis of unusual neoplasms, benignneoplasms, or diffuse hepatic or renal parenchymal diseases.

Even though needle biopsy is widely regarded as safe, often times leaksmay develop in the underlying tissues due to the needle puncture. Forexample, when conducting a needle biopsy of the lung, air leaks maydevelop, leading to collapse of the lung and/or pneumothorax. Theincidence of clinically significant pneumothorax following needle biopsyhas been reported to be in the 15-25% range. Needle biopsy also is usedto assess whether kidney transplantation has been successful, and isassociated with the formation of arteriovenous fistulae in 10-15% ofcases. Likewise, biopsy of the liver and spleen lead to bleedingcomplications in 5-10% of cases.

Liver biopsy is essential to the management of liver diseases. Althoughgenerally safe, the presence of a vascular tumor, bleeding diathesis orascites makes the procedure more hazardous. The development oftransvenous hepatic biopsy techniques have been one response to thisproblem. Prevention of hemorrhagic complications in high-risk patientshas been accomplished with different clinical methods, and with varyingdegrees of success. Several authors have suggested use of a transjugularroute for biopsy of the liver in high-risk patients. More recently,others have suggested that cutting needles may be used in conjunctionwith various methods to plug the needle track, for example, with steelembolization coils or gelatin sponge particles, such as GELFOAM®,manufactured by Upjohn, Inc., Kalamazoo, Mich.

U.S. Pat. No. 5,522,898 to Bao describes a closure device for the repairof skin tissue, controlling bleeding, and reducing the likelihood ofinducing excess scar tissue during a routine skin biopsy procedure,using a cylindrical tube made from a foam material which is absorbed ina biopsy site with little tissue reaction. That patent also describesthe use of GELFOAM® for topical applications. While GELFOAM® may beeffective in preventing bleeding, the sponge has a particulatestructure, and is difficult to inject smoothly down a needle track. Therisk of clumping and the subsequent scarcity of sponge along the needletrack presents a risk of bleeding after non-uniform embolization.

Chisholm et al., in “Fibrin Sealant as a Plug for the Post Liver BiopsyNeedle Track,” Clinical Radiology, 40:627-628 (1989) propose the use offibrin sealants to embolize a needle track. A drawback of thistechnique, however, is that fibrin sealants are associated with atheoretical risk of disease transmission due to the human and animalproteins that are the constituents of fibrin sealants.

Needle biopsies of other parenchymal tissues, such as kidney or lungtissue, also often result in prolonged hemorrhage or airleak from thesite of the biopsy. This especially may present a problem when multiplebiopsies are to be obtained from a particular organ.

It therefore would be desirable to provide hydrogel articles and methodsfor plugging voids created in tissue during surgical procedures, such asa needle track created during a biopsy, so as to reduce the risk ofhemorrhage after tissue removal.

Abusafieh et al., in “Development of Self-Anchoring Bone Implants. I.Processing and Material Characterization,” J. Biomed Mater Res.,38:314-327 (1997) describe the development of a self anchoring boneimplant formed by polymerizing hydrogels around carbon and KEVLAR®fibers, a registered trademark of E.I. DuPont de Nemours, Inc.,Wilmington, Del. The concept of self-anchoring swelling-type orthopedicimplants is described by Greenberg et al. in “Stimulation of BoneFormation by a Swelling Endosseous Implant,” J. Biomed Mater Res.,12:922-933 (1978). Such implants would, in principle, dilate in acontrolled manner by absorption of body fluids to achieve fixation by anexpansion-fit mechanism.

Although research on swelling-type bone implants began more than 15years ago, exploitation of this concept has been largely hampered by theinability to produce a material with the desired hydromechanicalproperties. None of the previously known materials are made fromabsorbable hydrogels and all are essentially permanent implants. Also,because there is a degradation in mechanical properties that accompaniesswelling, hydration for such materials has been restricted to less than5-8% by weight and takes place over long periods of time (several days).Since these previous known implants were intended for load bearingapplications, low hydration rates clearly were undesirable.

It therefore also would be desirable to provide methods of using andforming hydrogel articles that hydrate relatively quickly, and withoutsubstantial degradation of mechanical properties.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide methods of using hydrogel articles for sealing or occluding abody lumen, or tissue augmentation, that overcome the drawbacks ofpreviously known devices and methods. It is another object of thisinvention to provide methods of using and forming hydrogel articlescapable of undergoing a relatively large degree of swelling in-situ.

It is a further object of the present invention to provide methods ofusing and forming hydrogel articles for plugging voids created in tissueduring surgical procedures, such as a needle track created during abiopsy, so as to reduce the risk of hemorrhage after tissue removal.

It is yet another object of this invention to provide methods of usingand forming hydrogel articles that hydrate relatively quickly, andwithout substantial degradation of mechanical properties.

These and other objects of the invention are accomplished by providingmethods of using and forming medical articles from pharmaceuticallyacceptable hydrogel polymer, wherein the articles are introduced in adry, less hydrated, or substantially deswollen state, and rehydrate in aphysiological environment to increase in volume. The methods of thepresent invention may be advantageously used to affect sealing,plugging, or augmentation of tissue, defects in tissue and organs, andmay optionally permit controlled release of therapeutic agents at animplantation site. Hydrogel polymers useful for the present inventionmay be bioabsorbable or biostable, preferably exhibit a relatively largedegree of swelling and rapid rehydration rate, and may include any of avariety of pharmaceutically acceptable or implantable hydrogelbiomaterials of natural, recombinant, or of synthetic origin or hybridsthereof.

Methods to form medically useful devices in situ, and to implant devicesin accordance with the principles of the present invention in aminimally invasive fashion, also are provided.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention one or more rods, plugs,crushed or irregularly shaped pieces of substantially dehydratedhydrogel material are introduced into a lumen or void in a patient'sbody to seal or plug a biopsy needle track, serve to reinforce weaktissue, or deliver a therapeutic compound. The hydrogel polymerpreferably rehydrates rapidly, within a few minutes of being placed in amoist tissue environment, so as to anchor itself within tissue. Duringthe hydration process, the dried gel may expand volumetrically, e.g., inone, two or three dimensions, to several times its original size,thereby lodging the gel within the tissue and sealing against leakage offluids through the tissue.

This written description comprises the following portions: a descriptionof hydrogels suitable for use in practicing the methods of the presentinvention, descriptions of medical articles and methods for using thehydrogel articles of the present invention; and, example compositions ofhydrogel articles and exemplary applications.

I. Hydrogel Materials Suitable for Use in the Invention

Hydrogels may be formed from covalently or non-covalently crosslinkedmaterials, and may be non-degradable (“biostable”) in a physiologicalenvironment or broken down by natural processes within the body,referred to as biodegradable or bioabsorbable. The breakdown process maybe due to one of many factors in the physiological environment, such asenzymatic activity, heat, hydrolysis, or others, including a combinationof these factors.

Hydrogels that are crosslinked may be crosslinked by any of a variety oflinkages, which may be reversible or irreversible. Reversible linkagesmay be due to ionic interaction, hydrogen or dipole type interactions orthe presence of covalent bonds. Covalent linkages for absorbable ordegradable hydrogels may be chosen from any of a variety of linkagesthat are known to be unstable in an animal physiological environment dueto the presence of bonds that break either by hydrolysis (e.g., as foundin synthetic absorbable sutures), enzymatically degraded (e.g., as foundin collagen or glycosamino glycans or carbohydrates), or those that arethermally labile (e.g., azo or peroxy linkages).

All of the hydrogel materials appropriate for use in the presentinvention should be physiologically acceptable and should be swollen inthe presence of water. These characteristics allow the hydrogels to beintroduced into the body in a “substantially deswollen” state and over aperiod of time hydrate to fill a void, a defect in tissue, or create ahydrogel-filled void within a tissue or organ by mechanically exerting agentle force during expansion. The hydrogel may be preformed or formedin situ.

“Substantially deswollen” is defined as the state of a hydrogel whereinan increase in volume of the hydrogel of the article or device formed bysuch hydrogel is expected on introduction into the physiologicalenvironment. Thus, the hydrogel may be in a dry state, or less thanequilibrium hydrated state, or may be partially swollen with apharmaceutically acceptable fluid that is easily dispersed or is solublein the physiological environment. The expansion process also may causethe implanted material to become firmly lodged within a hole, anincision, a puncture, or any defect in tissue which may be congenital,diseased, or iatrogenic in origin, occlude a tubular or hollow organ, orsupport or augment tissue or organs for some therapeutic purpose.

Hydrogels useful in practicing the present invention maybe formed fromnatural, synthetic, or biosynthetic polymers. Natural polymers mayinclude glycosminoglycans, polysaccharides, proteins etc. The term“glycosaminoglycan” is intended to encompass complex polysaccharideswhich are not biologically active (i.e., not compounds such as ligandsor proteins) and have repeating units of either the same saccharidesubunit or two different saccharide subunits. Some examples ofglycosaminoglycans include dermatan sulfate, hyaluronic acid, thechondroitin sulfates, chitin, heparin, keratan sulfate, keratosulfate,and derivatives thereof.

In general, the glycosaminoglycans are extracted from a natural sourceand purified and derivatized. However, they also may be syntheticallyproduced or synthesized by modified microorganisms such as bacteria.These materials may be modified synthetically from a naturally solublestate to a partially soluble or water swellable or hydrogel state. Thismodification may be accomplished by various well-known techniques, suchas by conjugation or replacement of ionizable or hydrogen bondablefunctional groups such as carboxyl and/or hydroxyl or amine groups withother more hydrophobic groups.

For example, carboxyl groups on hyaluronic acid maybe esterified byalcohols to decrease the solubility of the hyaluronic acid. Suchprocesses are used by various manufacturers of hyaluronic acid products(such as Genzyme Corp., Cambridge, Mass.) to create hyaluronic acidbased sheets, fibers, and fabrics that form hydrogels. Other naturalpolysaccharides, such as carboxymethyl cellulose or oxidized regeneratedcellulose, natural gum, agar, agrose, sodium alginate, carrageenan,fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gumghatti, gum karaya, gum tragacanth, locust beam gum, arbinoglactan,pectin, amylopectin, gelatin, hydrophilic colloids such as carboxymethylcellulose gum or alginate gum cross-linked with a polyol such aspropylene glycol, and the like, also form hydrogels upon contact withaqueous surroundings.

Synthetic polymeric hydrogels generally swell or expand to a very highdegree, usually exhibiting a 2 to 100-fold volume increase uponhydration from a substantially dry or dehydrated state. Synthetichydrogels may be biostable or biodegradable or bioabsorbable. Biostablehydrophilic polymeric materials that form hydrogels useful forpracticing the present invention include poly(hydroxyalkylmethacrylate), poly(electrolyte complexes), poly(vinylacetate)cross-linked with hydrolysable bonds, and water-swellable N-vinyllactams.

Other suitable hydrogels include hydrophilic hydrogels know asCARBOPOL®, a registered trademark of B.F. Goodrich Co., Akron, Ohio, foracidic carboxy polymer (Carbomer resins are high molecular weight,allylpentaerythritol-crosslinked, acrylic acid-based polymers, modifiedwith C10-C30 alkyl acrylates), polyacrylamides marketed under theCYANAMER® name, a registered trademark of Cytec Technology Corp.,Wilmington, Del., polyacrylic acid marketed under the GOOD-RITE® name, aregistered trademark of B.F. Goodrich Co., Akron, Ohio, polyethyleneoxide, starch graft copolymers, acrylate polymer marketed under theAQUA-KEEP® name, a registered trademark of Sumitomo Seika Chemicals Co.,Japan, ester cross-linked polyglucan, and the like. Such hydrogels aredescribed, for example, in U.S. Pat. No. 3,640,741 to Etes, U.S. Pat.No. 3,865,108 to Hartop, U.S. Pat. No. 3,992,562 to Denzinger et al.,U.S. Pat. No. 4,002,173 to Manning et al., U.S. Pat. No. 4,014,335 toArnold and U.S. Pat. No. 4,207,893 to Michaels, all of which areincorporated herein by reference, and in Handbook of Common Polymers,(Scott & Roff, Eds.) Chemical Rubber Company, Cleveland, Ohio.

Hydrogels also may be formed to be responsive to changes inenvironmental factors, such as pH, temperature, ionic strength, charge,etc., by exhibiting a corresponding change in physical size or shape,so-called “smart” gels. For example, thermoreversible hydrogels, such asthose formed of amorphous N-substituted acrylamides in water, undergoreversible gelation when heated or cooled about certain temperatures(lower critical solution temperature, LCST). Prevailing gel formationmechanisms include molecular clustering of amorphous polymers andselective crystallization of mixed phases of crystalline materials. Suchgels, which are insoluble under physiological conditions, alsoadvantageously may be used for practicing the present invention.

It is also possible to affect the rate at which a substantiallydehydrated hydrogel rehydrates in a physiological environment, such asencountered upon implantation in an animal. For example, creating aporous structure within the hydrogel by incorporating a blowing agentduring the formation of the hydrogel may lead to more rapid re-hydrationdue to the enhanced surface area available for the water front todiffuse into the hydrogel structure.

When a foamed gel is desired, a two component mixture of the precursorsto a hydrogel forming system may be selected such that foaming andpolymerization to form the hydrogel are initiated when the two fluidchannels are mixed. A double barrel syringe assembly may be provided tomix the fluids, in which each barrel is equipped with a separate plungerto force the material contained therein out through a discharge opening.The plungers preferably are connected to one another at the proximalends so that a force exerted on the plungers generates equal pressurewithin each barrel and displaces both plungers an equal distance.

The hydrogel forming precursors for the foregoing system may be selectedso that, for example, a free radical polymerization is initiated whentwo components of a redox initiating system are brought together. One ofthese components additionally may include a foaming agent, e.g., sodiumbicarbonate, that when exposed to an acidic environment (e.g., the othercomponent in the syringe may comprise an acidic solution), releasescarbon dioxide as a foaming agent. While the effervescent compoundreacts with the water-soluble acid to release gases, the hydrogelstructure is polymerizing and crosslinking, thereby causing theformation of a stable foamed gel. Alternatively, other techniques, whichare per se known, may be used to foam the hydrogels.

In addition, the driving force for water to penetrate a dehydratedhydrogel also may be influenced by making the hydrogel hyperosmoticrelative to the surrounding physiological fluids. Incorporation ofcharged species within hydrogels, for example, is known to greatlyenhance the swellability of hydrogels. Thus the presence of carboxyl orsulfonic acid groups along polymeric chains within the hydrogelstructure may be used to enhance both degree and rate of hydration. Thesurface to volume ratio of the implanted hydrogels also is expected tohave an impact on the rate of swelling. For example, crushed driedhydrogel beads are expected to swell faster to the equilibrium watercontent state than a rod shaped implant of comparable volume.

Alternatively, instead of using dehydrated preformed hydrogels, in-situformed hydrogels formed from aqueous solutions of precursor moleculesalso may be used. The hydrogels may be absorbable or biostable. Theprecursor solutions preferably are selected so that the hydrogels whenformed in the physiological environment are below the equilibrium levelof hydration. Thus, when formed in-situ, the hydrogels have the abilityto hydrate and increase in size. If the hydrogels are formed in confinedtissue spaces, the additional swelling is expected to further anchor thehydrogel in place.

Any of a variety of techniques may be used to form hydrogels in-situ.For example, monomers or macromers of hydrogel forming compositions maybe further polymerized to form three dimensionally cross-linkedhydrogels. The crosslinking may be covalent, ionic, and or physical innature. Polymerization mechanisms permitting in-situ formation ofhydrogels are per se known, and include, without limitation, freeradical, condensation, anionic, or cationic polymerizations. Thehydrogels also may be formed by reactions between nucleophilic andelectrophilic functional groups, present on one or more polymericspecies, that are added either simultaneously or sequentially. Theformation of hydrogels also may be facilitated using external energysources, such as in photoactivation, thermal activation and chemicalactivation techniques.

Absorbable Polymeric Hydrogels

Absorbable polymers, often referred to as biodegradable polymers, havebeen used clinically in sutures and allied surgical augmentation devicesto eliminate the need for a second surgical procedure to removefunctionally equivalent non-absorbable devices. See, for example, U.S.Pat. No. 3,991,766 to Schmitt et al. and Shalaby, Encyclopedia ofPharmaceutical Technology (Boylan & Swarbrick, Eds.), Vol. 1, Dekker,New York, 1988, p. 465. Although these previously known devices wereintended for repairing soft tissues, interest in using such transientsystems, with or without biologically active components, in dental andorthopedic applications has grown significantly in the past few years.Applications of absorbable polymers are disclosed in Bhatia, et al., J.Biomater. Sci., Polym. Ed., 6(5):435 (1994), U.S. Pat. No. 5,198,220 toDamani, U.S. Pat. No. 5,171,148 to Wasserman, et. al., and U.S. Pat. No.3,991,766 to Schmitt et al.

Synthesis and biomedical and pharmaceutical applications of absorbableor biodegradable hydrogels based on covalently crosslinked networkscomprising polypeptide or polyester components as the enzymatically orhydrolytically labile components, respectively, have been described by anumber of researchers. See, e.g., Jarrett et al., “BioabsorbableHydrogel Tissue Barrier: In Situ Gelation Kinetics,” Trans. Soc.Biomater., Vol. XVIII, 182 (1995); Sawhney et al., “BioerodibleHydrogels Based on PhotopolymerizedPoly(ethyleneglycol)-co-poly(α-hydroxy acid) Diacrylate Macromers”,Macromolecules, 26:581-587 (1993); Park, et al., Biodegradable Hydrogelsfor Drug Delivery, Technomic Pub. Co., Lancaster, Pa. (1993); Park,“Enzyme-digestible swelling hydrogels as platforms for long-term oraldelivery: synthesis and characterization,” Biomaterials, 9:435-441(1988). The hydrogels most often cited in the literature are those madeof water-soluble polymers, such as polyvinyl pyrrolidone, which havebeen crosslinked with naturally derived biodegradable components such asthose based on albumin.

Totally synthetic hydrogels have been studied for controlled drugrelease and membranes for the treatment of post-surgical adhesion. Thosehydrogels are based on covalent networks formed by the additionpolymerization of acrylic-terminated, water-soluble polymers that haveat least one biodegradable spacer group separating the water solublesegments from the crosslinkable segments, so that the polymerizedhydrogels degrade in vivo. Such hydrogels are described in U.S. Pat. No.5,410,016, which is incorporated herein by reference, and may beparticularly useful for practicing the present invention.

Preferred hydrogels for use in the present invention are formed by thepolymerization of macromers that form hydrogel compositions that areabsorbable in vivo. These macromers, for example, may be selected fromcompositions that are biodegradable, polymerizable, and substantiallywater soluble macromers comprising at least one water soluble region, atleast one degradable region, and statistically more than 1 polymerizableregion on average per macromer chain, wherein the polymerizable regionsare separated from each other by at least one degradable region.

Hydrogels that have some mechanical integrity and that cannot be“extruded” from the implantation site by forces applied by naturalmovement of surrounding tissues are preferred for this invention. Thus,hydrogels suitable for use in the present invention preferably arephysically or chemically crosslinked, so that they possess some level ofmechanical integrity even when fully hydrated. The mechanical integrityof the hydrogels may be characterized by the tensile modulus at breakingfor the particular hydrogel. Hydrogels having a tensile strength inexcess of 10 KPa are preferred, and hydrogels having a tensile strengthgreater than 50 KPa are more preferred.

II. Applications for in-Situ Hydration

A number of applications of the foregoing hydrogels are described inaccordance with the principles of the present invention. Moreparticularly, use of hydrogel medical articles are described fornumerous applications wherein the article inserted with a small profile,and upon hydration serves to occlude lumens, augment tissues or organs,or block orifices.

1. Sealing of Biopsy Tracks

Biopsy needle tracks may be embolized in accordance with the principlesof the present invention to reduce complications associated with needlebiopsies, such as bleeding and airleaks. A preformed plug of a hydrogelselected as described hereinabove may be placed in a needle track, forexample, using the same device that was used for the tissue retrieval.

Specifically, the hydrogel plug is formed from a material exhibitingrapid hydration and swelling, and a low degree of syneresis, i.e., itdoes not allow absorbed fluid to be easily expelled under moderatemechanical loading. The hydrogel plug may be preformed and partially orcompletely dehydrated. Upon completion of a biopsy, the hydrogel plug isdisposed in the needle track formed by the biopsy instrument. The plugthen rehydrates and swells to become firmly lodged in the needle track.The hydrogel plug preferably is bioabsorbable, so that it may beabsorbed and allow tissue to eventually fill the needle track.Alternatively, the hydrogel may be formed in-situ, as describedhereinabove.

2. Bone Plugs

Bone plugs often are used to occlude the femoral canal during hipreplacement surgery. Restricting the escape of uncured bone cementduring the insertion of the femoral prosthesis is known to improvepenetration of the cement into adjacent spongy bone and ensure completefilling of the canal, including beneath the tip of the device. Pluggingthe medullary canal prior to cement insertion also aids in compactingthe bone cement to eliminate internal voids that may cause cracking andfailure of the cement. Apart from the initial cement insertion process,this application is not a load bearing one and is thus ideally suited tothe use of an absorbable hydrogel plug. After the cement has set up,within a few hours, the load is borne by the cement.

A rapidly hydrating hydrogel plug that has a “one size fits all”capability for intermedullary canals and that does not need any specialtools for insertion (drop fit only), may be a convenient tool fororthopedic surgeons. It is expected that a plug of substantiallydehydrated hydrogel material may be introduced into the intramedullarycanal after the reaming process is complete. The plug will rehydratewithin a few minutes to generate a fit sufficiently tight to preventleakage of the bone cement. Such bone plugs are expected to havesignificant benefits over previously known non-degradable polyethyleneplugs, which form permanent implants.

3. Suture Anchors

Hydrogel articles prepared in accordance with the principles of thepresent invention may be advantageously employed as bone or cartilageanchors. Suture anchors play an increasingly important role in attachingtendons or ligaments to bone, and are typically made of metallic orother nonbioabsorbable materials. Non-loadbearing indications, such asdelicate maxofacial reconstruction or repair of cartilage tears, alsomay benefit from a soft hydrogel-type absorbable suture anchor. The selfhydrating and tightening characteristic of hydrogels may advantageouslyreduce problems of anchor loosening, migration, interference withimaging studies, and the potential requirement for later implantremoval.

For this and the preceding applications, hydrogel material may bethreaded or formed around nonabsorbable or absorbable polymer sutures toallow accurate guidance and placement of the devices. In thesubstantially dehydrated state the suture has a good holding or“potting” strength within the hydrogel article. Upon hydration of thehydrogel material, after the hydrogel is expected to be securelyanchored at the surgical site of interest, the suture material easilymay be removed. Sutures potted within the hydrogel articles may includesingle or composite fibers. The shape, form and diameter of the fibermay vary, and may include monofilament, multifilament, twisted thread,spun yarn, staple fiber and whisker.

4. Dental Applications

Hydrogel articles of the present invention also may be advantageouslyused in dentistry, for example, in occluding root canals. Generally,after a root canal has been cleaned and disinfected, the resultingpassageway is occluded to prevent bacterial contamination. Oftenun-crosslinked rubber-type materials, such as Gutta-Percha, are used toplug these openings. Gutta-Percha, however, has no inherent form-fittingproperty and must be mechanically forced into the canal.

In accordance with the principles of the present invention, a rod ofsubstantially dehydrated hydrogel material may be cut to size andintroduced into the root canal, where it is allowed to hydrate, swell,and lock into place to form a tight fit. The hydrogel is expected toprovide an effective barrier against oral fluids, food material, andbacteria. If a substantially non-degradable hydrogel is selected, longterm occlusion may be provided. Alternatively, an absorbable materialmay be used if it is desirable that natural tissues replace the hydrogelover a period of time.

5. Wound Closure

Hydrogel articles of the present invention may be employed for closureof percutaneous catheter puncture sites. Most angiographic, angioplasty,and a variety of other less-invasive catheter based approaches to thevascular system are carried out by cannulating the femoral artery.Generally, a sheath is positioned through a puncture wound to provideaccess to the artery and allow exchange of various catheters requiredduring a procedure. At the end of the procedure, the sheath is removed,often resulting in a considerable amount of bleeding.

In accordance with well-known techniques, manual pressure is applied tothe wound for a period of about 30 to 60 minutes to prevent bleeding andallow cessation of bleeding by clot formation. Even when a clot hasformed, the patient is not permitted to freely move around for fear ofre-bleeding. Several medical devices, based on collagen-type materials,have been developed to fill the space or track left by the sheath. Thesematerials are however, inherently inflammatory and pro-thrombotic, andmay promote intimal hyperplasia or thrombosis of the artery. Whilevarious suturing techniques have been developed that use long needles,suture material, and knot pushing devices have been used to close thearteriotomy site, these techniques require considerable skill,especially where visualization of the site is limited.

Hydrogel articles of the present invention may be advantageously used toovercome the drawbacks of previously known wound closure systems. Forexample, a rod-shaped plug of a substantially desiccated hydrogel may bedeployed into the site of an arteriotomy and allowed to hydrate, in thepresence of the tissue fluids and blood, to rapidly fill the track ofthe catheter sheath and prevent further bleeding. By swelling toequilibrium hydration, the plug will lock itself firmly in place andthus reduce the risk of formation of a large hematoma at the site of thepuncture.

A hydrogel rod also may be used in conjunction with a pledget configuredfor intraarterial placement, and that has a suture connecting it to thehydrogel rod. A pledget is a small thin resilient object, formed frompolyester foam or felt, that is used to distribute a load imposed by asuture strand to surrounding tissue to prevent tearing, or to reducebleeding at a puncture site. In this case, the pledget actually providesthe arterial closure, but is anchored by the swollen hydrogel within thepuncture site. The hydrogel itself may consist of a single rod oralternatively, may comprise a combination of hydrogel shapes, such asbraided strands, etc. In the latter case, the resulting macroporousspaces and larger surface area are expected to permit more rapidhydration.

6. Occlusion of Arteriovenous Malformations

Hydrogel articles of the present invention may be introduced into apatient's body in a low profile, substantially dehydrated state, suchthat upon hydration the hydrogel article occludes an abnormal vascularstructure. Abnormal vascular connections, known as arteriovenousmalformations (AVMs), may develop either as a congenital defect or as aresult of iatrogenic or other trauma. An AVM may lead to a substantialdiversion of blood from the intended tissue and may consequentlyengender a variety of symptoms, including those leading to morbidity.Subdural hematomas and bleeding also may occur as a result of thepresence of an AVM.

Surgical intervention is often undertaken to correct AVMs.Interventional radiologic approaches also are used to obliterate AVMs byembolization, in which the goal of embolization is to selectivelyobliterate an abnormal vascular structure, while preserving blood supplyto surrounding normal tissues. Embolization typically is accomplishedusing low-profile soft microcatheters that allow superselectivecatheterization into the brain to deliver an embolic material underfluoroscopic guidance. Various embolic materials have been used inendovascular treatment in the central nervous system, such ascyanoacrylates, ethylene-vinyl alcohol copolymer mixtures (EVAL),ethanol, estrogen, poly(vinyl acetate), cellulose acetate polymer, poly(vinyl alcohol) (PVA), gelatin sponges, microfibrillar collagen,surgical silk sutures, detachable balloons, and coils.

In accordance with the principles of the present invention,substantially dry hydrogel materials may be introduced with a catheterunder radiographic guidance to embolize AVMs. Upon delivery to thevascular network, the hydrogel articles, which may be in rod, pellet,fiber, rolled up film or other physical form, rehydrate and occlude thevascular flow by mechanical obstruction. Preferred hydrogel materials tobe used in this application should be biostable and not be degraded bythe vascular environment. Where permanent embolization is desired,non-degradable hydrogel materials are preferred over degradable ones.

7. Occlusion of Reproductive Organs

Hydrogel articles also may be introduced into the body in a low profilein a substantially dehydrated state such that, upon hydration, theyocclude lumens of reproductive structures. For example, the World HealthOrganization has underscored the need for a rapid and minimally invasivemethod for female sterilization. Most sterilization techniques usedcurrently are invasive and irreversible. Approximately 40-50% of womenage 15-44 that choose to use a contraceptive method are sterilized ortheir husband has undergone sterilization.

Lack of reversibility and the need for a surgical procedure are majordrawbacks of previously known sterilization methods. Ligation offallopian tubes must to be conducted under epidural anesthesia and is adifficult procedure to reverse. Recently developed scarificationtechniques involving off-label intrauterine use of Quinacrine have beenassociated with morbidity and even mortality. There is, therefore a needfor a safe and effective way to induce sterilization with a retainedoption of reversibility.

Catheters to determine the patency of fallopian tubes have beendeveloped, for example by Conceptus Inc., San Carlos, Calif. Ultrasonicinspection for determining the patency of fallopian tubes is awell-known procedure. In accordance with one aspect of the presentinvention, deswollen hydrogel plug may be inserted intrauterally intothe fallopian tubes. When the plugs rehydrate, they occlude thefallopian tubes and readily effect sterilization.

The use of substantially dehydrated hydrogels may permit such hydrogelplugs to be deployed in a doctor's office setting, without the need foranesthesia. If fertility is to be restored later, the hydrogel plugs maybe comprise a biodegradable material that undergoes natural degradationin the physiological environment. Alternatively, the hydrogel plugs maybe removed by administration of a solvating agent, or by mechanicalremoval, and the patency of the tubes restored and confirmed byultrasound.

8. Sphincter Augmentation

It is estimated that at least 30 million Americans suffer from urinaryincontinence. Urinary incontinence may be either temporary or permanent,and result from physiologic or neurologic deficits. Female stressincontinence, i.e., the loss of urine during everyday activities such aslaughing, sneezing, coughing, etc., is the most common type ofincontinence, and generally responds better to surgery than topreviously known drug therapies.

Several surgical approaches have been adopted for the correction offemale stress incontinence including urethral slings, bladder necksuspensions, and artificial sphincter implantation. A recent approach tosphincter augmentation uses an injectable collagen as a urethral bulkingagent to correct intrinsic sphincter deficiency. Unfortunately, it hasbeen observed that the collagen is resorbed in up to 20% of women within9 months. Because the procedure is conducted in a minimally invasivefashion, it provides an attractive alternative to intraoperativesolutions. There remains, however, a need for a more permanent way toaugment the urinary sphincter with a percutaneously administeredbiocompatible in-situ formed bulking agent and that does not raise posethe safety risks associated with collagen.

In accordance with another aspect of the present invention,substantially dehydrated hydrogels may be percutaneously implanted intothe urethral sphincter to create an elastic and tissue-like bulk thatlasts several years. Any of the variety of hydrogels describedhereinabove have the persistence and in vivo biocompatibilitycharacteristics to be suitable for this process.

A similar approach also may be used to correct other sphincterdeficiencies. For example, the gastro-esophageal sphincter may bepercutaneously augmented to reduce gastric reflux. The pyloric sphincteralso may be percutaneously augmented to reduce “dumping” problemsassociated with intestinal pH imbalance.

9. Medical Device Coating

In accordance with another aspect of the present invention,substantially dehydrated hydrogel may be used to coat a medical device,so that hydration of the coating enables the medical device to becomeanchored in place to prevent migration. For example, stent grafts arewire mesh type devices that are used in conjunction with a textile typewoven, knit, or film type material. The wire framework mechanically holda lumen, e.g., an artery, open, while the textile, fabric, or filmprovides a lumen through which fluids may flow. This approach has beensuccessfully used in treating aneurysms, such as abdominal aorticaneurysms.

A significant shortcoming of previously known stent grafts systems,however, has been the leakage of blood around the stent graft. Thisbypass flow often causes the aneurysm to further increase in size, andmay lead to eventual rupture.

In accordance with the principles of the present invention, asubstantially dehydrated hydrogel coating is disposed on the exteriorsurface of the textile, fabric, or film of the stent graft. Whendeployed in a body lumen, the coating hydrates in the presence of bloodand tightly wedges the stent graft in position. In addition, as thehydrogel hydrates it causes the stent graft to closely conform to theboundaries of the vessel, so that the blood leakage around the stentgraft may be reduced.

10. Delivery of Drugs and Therapeutic Entities

Often the reason for performing a biopsy is the presence of a suspectedtumor or other mass of diseased tissue. After confirmation of the biopsyidentity, it may be desirable to place a therapeutic agent at the siteof suspected disease. The self-anchoring swellable hydrogel articles ofthe present invention may enable the delivery of therapeutic entities tosuch sites through the same channel as the instrument that is used toperform the biopsy (or with an instrument having a similar profile).

Optionally, a hydrogel plug, such as described hereinabove, may includeone or more biologically-active agents and elute the agent to adjacentor distant tissues and organs in the animal. Biologically-active agentssuitable for use include, for example, medicaments, drugs, or othersuitable biologically-, physiologically-, or pharmaceutically-activesubstances that provide local or systemic biological, physiological ortherapeutic effect in the body of an animal including a mammal.

Water-soluble drugs that may be incorporated within the hydrogelarticles of the present include, for example, peptides having biologicalactivities, other antibiotics, antitumor agents, antipyretics,analgesics, anti-inflammatory agents, antitussive expectorants,sedatives, muscle relaxants, antiepileptic agents, antiulcer agents,antidepressants, antiallergic agents, cardiotonics, antiarrhythmicagents, vasodilators, hypotensive diuretics, antidiabetic agents,anticoagulants, hemostatics, antituberculous agents, hormonepreparations, narcotic antagonists, bone resorption inhibitors,angiogenesis inhibitors and the like.

Examples of the foregoing antitumor agents include bleomycinhydrochloride, methotrexate, actinomycin D, mitomycin C, vinblastinesulfate, vincristine sulfate, daunorubicin hydrochloride, adriamycin,neocarzinoszatin, cytosine arabinoside, fluorouracil,tetrahydrofuryl-5-fluorouracil krestin, picibanil, lentinan, levamisole,bestatin, azimexon, glycyrrhizin, poly I:C, poly A:U, poly ICLC,cisplatin and the like.

The biologically-active agent may be soluble in the polymer solution toform a homogeneous mixture, or insoluble in the polymer solution to forma suspension or dispersion. Upon implantation, the biologically-activeagent preferably becomes incorporated into the implant matrix. As thematrix degrades over time, the biologically-active agent is releasedfrom the matrix into the adjacent tissue fluids, preferably at acontrolled rate. The release of the biologically-active agent from thematrix may be varied, for example, by the solubility of thebiologically-active agent in an aqueous medium, the distribution of theagent within the matrix, the size, shape, porosity, solubility andbiodegradability of the implant matrix, and the like.

The biologically-active agent may stimulate a biological orphysiological activity with the animal. For example, the agent may actto enhance cell growth and tissue regeneration, function in birthcontrol, cause nerve stimulation or bone growth, and the like. Examplesof useful biologically-active agents include a substance, or metabolicprecursor thereof, that promotes growth and survival of cells andtissues, or augments the functioning of cells, as for example, a nervegrowth promoting substance such as a ganglioside, a nerve growth factor,and the like; a hard or soft tissue growth promoting agent such asfibronectin (FN), human growth hormone (HGH), protein growth factorinterleukin-1 (IL-1), and the like; a bone growth promoting substancesuch as hydroxyapatite, tricalcium phosphate, and the like; and asubstance useful in preventing infection at the implant site, as forexample, an antiviral agent such as vidarabine or acyclovir, anantibacterial agent such as a penicillin or tetracycline, andantiparasitic agent such as quinacrine or chloroquine.

Suitable biologically-active agents for use in the present inventionalso include anti-inflammatory agents such as hydrocortisone, prednisoneand the like; antibacterial agents such as penicillin, cephalosporins,bacitracin and the like; antiparasitic agents such as quinacrine,chloroquine and the like; antifungal agents such as nystatin,gentamicin, and the like; antiviral agents such as acyclovir, ribavirin,interferons and the like; antineoplastic agents such as methotrexate,5-fluorouracil, adriamycin, tumor-specific antibodies conjugated totoxins, tumor necrosis factor, and the like; analgesic agents such assalicylic acid, acetaminophen, ibuprofen, flurbiprofen, morphine and thelike; local anesthetics such as lidocaine, bupivacaine, benzocaine andthe like; vaccines such as hepatitis, influenza, measles, rubella,tetanus, polio, rabies and the like; central nervous system agents suchas a tranquilizer, B-adrenergic blocking agent, dopamine and the like;growth factors such as colony stimulating factor, platelet-derivedgrowth factors, fibroblast growth factor, transforming growth factor B,human growth hormone, bone morphogenetic protein, insulin-like growthfactor and the like; hormones such as progesterone, follicle stimulatinghormone, insulin, somatotropins and the like; antihistamines such asdiphenhydramine, chlorphencramine and the like; cardiovascular agentssuch as digitalis, nitroglycerine, papaverine, streptokinase and thelike; vasodilators such as theophylline, niacin, minoxidil, and thelike; and other like substances.

Therapeutic agents that may be delivered may include for example,physiologically active materials or medicinal drugs (such as agentsaffecting central nervous system, antiallergic agents, cardiovascularagents, agents affecting respiratory organs, agents affecting digestiveorgans, hormone preparations, agents affecting metabolism, antitumoragents, antibiotic preparations, chemotherapeutics, antimicrobials,local anesthetics, antihistaminics, antiphlogistics, astringents,vitamins, antifungal agents, peripheral nervous anesthetics,vasodilators, crude drug essences, tinctures, crude drug powders,hypotensive agents, and the like).

The terms “cytokine” and “growth factor” are used to describebiologically active molecules and active peptides (which may be eithernaturally occurring or synthetic) that aid in healing or regrowth ofnormal tissue, including growth factors and active peptides. Thefunction of cytokines is two-fold: 1) to incite local cells to producenew collagen or tissue, or 2) to attract cells to the site in need ofcorrection. As such, cytokines and growth factors serve to encourage“biological anchoring” of the implant within the host tissue. Aspreviously described, the cytokines may be admixed with the conjugate orchemically coupled to the conjugate.

For example, one may incorporate cytokines such as interferons (IFN),tumor necrosis factors (TNF), interleukins, colony stimulating factors(CSFs), or growth factors such as osteogenic factor extract (OFE),epidermal growth factor (EGF), transforming growth factor (TGF) alpha,TGF-β_(including any combination of TGF-βs), TGF-β1, TGF-β2, plateletderived growth factor (PDGF-AA, PDGF-AB, PDGF-BB), acidic fibroblastgrowth factor (FGF), basic FGF, connective tissue activating peptides(CTAP), β-thromboglobulin, insulin-like growth factors, erythropoietin(EPO), nerve growth factor (NGF), bone morphogenic protein (BMP),osteogenic factors, and the like.

The hydrogels of the present invention also may provide controlleddelivery of various antibiotics, including, for example,aminoglycosides, macrolides such as erythromycin, penicillins,cephalosporins and the like; anesthetic/analgesic delivery pre-or postsurgery or to treat pain using such agents as amide-type localanesthetics like lidocaine, mepivacaine, pyrrocaine, bupivacaine,prilocaine, etidocaine, or the like; and local controlled delivery ofnon-steroidal anti-inflammatory drugs such as ketorolac, naproxen,diclofenac sodium and flurbiprofen.

In certain forms of therapy, the same delivery system, i.e., hydrogelarticle, may be used to deliver combinations of agents/drugs to obtainan optimal effect. Thus, for example, an antibacterial and ananti-inflammatory agent may be combined in a single polymer to providecombined effectiveness.

Particular water-soluble polypeptides that may be used in the hydrogelarticles of the present invention include, for example, oxytocin,vasopressin, adrenocorticotrophic hormone (ACTH), epidermal growthfactor (EGF), transforming growth factor antagonists, prolactin,luliberin or luteinizing hormone releasing hormone (LH-RH), LH-RHagonists or antagonists, growth hormone, growth hormone releasingfactor, insulin, somatostatin, bombesin antagonists, glucagon,interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin,calcitonin, enkephalins, endomorphins, angiotensins, renin, bradykinin,bacitracins, polymyzins, colistins, tyrocidin, gramicidines, andsynthetic analogues and modifications and pharmaceutically-activefragments thereof, monoclonal antibodies and soluble vaccines.

Other beneficial drugs are known in the art, as described inPharmaceutical Sciences, by Remington, 14th Ed., Mack Publishing Co.(1979); The Drug, The Nurse, The Patient, Including Current DrugHandbook, by Falconer et al., Saunder Company (1974-76); and MedicinalChemistry, 3rd Ed., Vol. 1 and 2, by Burger, Wiley-Interscience Co.

The hydrogel polymers of the present invention may be designed torelease appropriate encapsulated, or uncapsulated, growth factors,including epidermal growth factors, human platelet derived TGF-β,endothelial cell growth factors, thymocytic-activating factors, plateletderived growth factors, fibroblast growth factor, fibronectin orlaminin.

Useful release rate modification agents may be dissolved or dispersedwithin the hydrogel material, and include, for example, organicsubstances that are water-soluble, water-miscible, or water-insoluble(i.e., water immiscible), with water-insoluble substances preferred. Therelease rate modification agent preferably is an organic compound thatsubstitutes as the complementary molecule for secondary valence bondingbetween polymer molecules, and increases the flexibility and ability ofthe polymer molecules to slide past each other. Such an organic compoundpreferably includes a hydrophobic and a hydrophilic region so as toeffect secondary valence bonding. Preferably, the release ratemodification agent is compatible with the combination of polymers andsolvent used to formulate polymer solution. It is further preferred thatthe release rate modification agent be a pharmaceutically-acceptablesubstance.

Useful release rate modification agents include, for example, fattyacids, triglycerides, other like hydrophobic compounds, organicsolvents, plasticizing compounds and hydrophilic compounds. Suitablerelease rate modification agents include, for example, esters of mono-,di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, methylacetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutylphthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate,dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyltriethyl citrate, glycerol triacetate, di(n-butyl) sebecate, and thelike; polyhydroxy alcohols, such as propylene glycol, polyethyleneglycol, glycerin, sorbitol, and the like; fatty acids; triesters ofglycerol, such as triglycerides, epoxidized soybean oil, and otherepoxidized vegetable oils; sterols, such as cholesterol; alcohols, suchas C₆-C₁₂ alkanols, 2-ethoxyethanol, and the like.

The release rate modification agent may be used singly or in combinationwith other such agents. Suitable combinations of release ratemodification agents include, for example, glycerin/propylene glycol,sorbitol/glycerine, ethylene oxide/propylene oxide, butyleneglycol/adipic acid, and the like. Preferred release rate modificationagents include dimethyl citrate, triethyl citrate, ethyl heptanoate,glycerin, and hexanediol.

III. EXAMPLES Example 1

Formation of Deswollen Hydrogel Rods

Hydrogels may be made using a poly(ethylene glycol) diacrylatemacromonomer (M.W. 20,000) at a concentration of 10%. 3 μl/ml of aphotoinitiator solution, such as Irgacure 651, available from CibaSpecialty Chemicals Corp., Switzerland, dissolved in N-vinylpyrrolidinone at a concentration of 0.6 g/ml) is added to the macromersolution. The solution may be injected into hollow glass tubes with aninner diameter of 4 mm and illuminated with ultraviolet light from aBlak Ray B-100A lamp for 1 min. The polymerized rods are then extrudedfrom the glass tubes and allowed to dry in an oven at 60□C for 24 hrs.At the end of this period the rods should have substantially shrunk inoverall size. When placed in an aqueous environment (such asphysiological saline) the rods should hydrate within 15-30 minutes toseveral times the dried size.

Example 2

Use of Hydrogel Rods to Seal Parenchymal Lung Tissue

A freshly explanted pig lung is cored to retrieve a biopsy of lungparenchymal tissue using a side cutting biopsy needle (CookIncorporated, Bloomington, Ind.). On inflation of the lung with anambulatory bag an airleak should be evident at the site of the needlebiopsy. A rod-shaped hydrogel article prepared according to Example 1 isplaced within the site of the needle puncture. The natural tissue fluidsand moisture present in the needle puncture will cause the driedhydrogel to rehydrate over a few minutes to effectively plug theairleak. On subsequent inflation, no airleak should be evident and therod of hydrogel should be firmly lodged within the needle track.

Example 3

Enhancement of Rate of Hydration

It is possible to enhance the swelling rate by making the dried hydrogelhypertonic by the addition of water soluble salts or other agents,including solvents or low molecular weight excipients or oligomers. Suchagents rapidly dissolve in an aqueous setting and generate an osmoticdriving force that accelerates the hydration process.

Example 4

Further Enhancement of Rate of Hydration

Macro- or microporosity or surface texture may be created in thehydrogels to increase the surface area for ingress of aqueous fluids,thereby enhancing hydration or control of hydration. Pores formed in thedried hydrogel may create capillary forces that, i.e., a sponge-likeeffect, to cause rapid absorption of water and concomitant rapidexpansion and deployment of the hydrogel.

Example 5

Further Enhancement of Rate of Hydration

The molecular weight between crosslinks may be used as a measure tocontrol the rate of hydration. Thus, hydrogels may be prepared asdescribed in Example 1 with PEG diacrylate macromers of varyingmolecular weights. The lower molecular weight macromers should yield amore rapid hydration, while the higher molecular weigh macromers shouldyield a slower hydration. This result obtains because the longersegments in between crosslinks that take longer to unravel completely.This phenomena also may lead to a greater total hydration for the highermolecular weight hydrogels compared to the lower molecular weighthydrogels.

Example 6

Use of Natural Hydrogel Materials

A sheet of a hydrogel forming natural material, such as SEPRAFILM™,marketed by Genzyme Corporation, Cambridge, Mass., is trimmed to form apiece approximately 2 cm square. The piece is rolled from one edge tothe other to form a “carpet roll”. The roll then may be inserted into aneedle biopsy track, as described in Example 2. Hydration of the sheetover a few minutes is expected to resulted in an effective sealing ofthe site of airleak. Since the SEPRAFILM™ material is known to bebioabsorbed over a few weeks, it is expected that, in vivo, the lungtissues will heal around this material as it undergoes bioabsorption,thus forming a permanent seal even after absorption of the material.

Example 7

Use of a Suture Embedded within the Hydrogel

A hydrogel rod is formed as described in Example 1, except that suturematerial (e.g., 3-O VICRYL®, available from Ethicon, Inc., NewBrunswick, N.J.) is placed within the macromer solution in a hollowglass tube that has an inner diameter of 1.5 cm. The suture may beplaced within the macromer solution prior to polymerization, so that thehydrogel formed by polymerization contains the distal end of the sutureembedded in it, while the proximal end of the suture is free formanipulation. When dried, the suture should be firmly embedded withinthe hydrogel rod, enabling the rod of hydrogel to be easily manipulatedusing the suture.

Example 8

Use of a Suture Embedded Hydrogel as a Bone Plug

A rod of dried hydrogel that contains an embedded suture is prepared asdescribed in Example 7. A lamb femur bone is obtained from an abattoir.The distal 5 cm of the bone may be sawed off to expose theintramedullary canal. The intramedullary canal is drilled to simulate aprocedure wherein a hip stem is implanted and fixed with a bone cement.The rod of dried hydrogel may be maneuvered 3 cm deep within theintramedullary canal until satisfactory placement depth is obtained bymeasuring the suture length remaining outside the femur.

Saline solution then is instilled within the intramedullary canal andthe hydrogel allowed to hydrate until it is found to have formed anadequate friction fit within the bone. At this stage the suture may beeasily retrieved, because its holding strength within the hydrated gelshould be lower than that in the dried hydrogel. Subsequent instillationof bone cement within the cavity may be used to verify that an effectiveplugging of the intramedullary canal has been achieved.

Example 9

Use of a Hydrogel as a Cervical Canal Plug

A hydrogel plug selected in accordance with the principles of thepresent invention advantageously may be used to plug a cervical canalfollowing a tear in the amniotic membrane, which otherwise might lead toa forced pre-term birth. A plug about 3-4 mm in diameter is used toblock the cervical opening to prevent fluid drainage or leakage. Theplug should fall out when the cervix dilates naturally for normal birthand then may be easily removed.

Example 10

Use of a Hydrogel Coating on Sutures

A braided suture material (5-O Vicryl, available from Ethicon Inc., NewBrunswick, N.J.) is dipped in the photopolymerizable macromer solutiondescribed in Example 1. Excess macromer solution may be removed until athin coating about 50-100 μm remains. The suture then is exposed to longwave ultraviolet light to polymerize the hydrogel around the suturematerial. The suture is allowed to dry in an oven at 50° C. overnight.

An arterial anastamosis of a porcine carotid artery maybe performedusing either the coated suture or, as a control, uncoated suturematerial. The arteries are perfused with saline at a pressure of 120 mmHg for 15 minutes with saline that contains a dye (methylene blue, 0.2mg/ml). Initially, both anastamoses should be found to ooze through thesuture line needle holes. This is expected, because the needle typicallyhas a larger diameter than the suture, resulting in a hole that islarger in size than the suture left behind in the tissue. Within 5minutes, the coated suture line should have sealed the needle holes dueto the hydration of the coating, while the control suture line shouldcontinue to ooze.

Example 11

Use of a Hydrogel Plug for Occlusive Sterilization

Occlusion of lumens of the reproductive systems may be effected toaccomplish male/female sterilization. For instance, the fallopian tubesof a woman may be occluded to obstruct the path of the egg, while in menthe vas deferens may be occluded to interrupt the passage of spermthrough the spermatic duct. Such occlusion of lumens may be accomplishedusing rods of dried up hydrogels that are placed within the lumen andare allowed to rehydrate in the presence of moisture (in the body),increase in volume, and gradually occlude the lumen. In order to preventmigration of the hydrogel plugs, the diameters of the hydrogel plugs atequilibrium hydration may be selected to be larger than the lumen to beoccluded. The hydrogel rods also may include a radio-opaque contrastagent to assist in placing the plugs. Further, the hydrogel plugs may beformed from absorbable hydrogels, to provide reversible sterilization.Alternatively, alginate-based gels that have been crosslinked withcalcium may be used to form hydrogel plugs. Such plugs may be reinforcedwith an interior mesh or matrix and include a short anchoring suture.The hydrogel plugs may be dried (or freeze dried to allow rapidrehydration), and would swell upon placement within the lumen to occludethe lumen. For reversal of sterilization, a solution of citric acid maybe administered intrauterally to redissolve the plugs and restorepatency, as confirmed, for example, by dye instillation.

Example 12

Use of a Hydrogel Plug to Close a Bronchial Fistula

A hydrogel rod is formed as described in Example 8, except that the rodis formed in a mold 5 mm in diameter and has a 50 cm long sutureembedded in it. The hydrogel is dried to a diameter of about 1.5 mm. Thehydrogel may be placed in a catheter comprising a hollow flexible tubewith a distal opening and a proximal end that remains outside thepatient. The distal end may be maneuvered through the operating channelof a bronchoscope and into the bronchial tree to implant the hydrogelrod.

In an explanted porcine lung, a fistula may be created by incising asegmental bronchus in the left lower lobe. Airleaks should be apparentwhen the lung is forcibly ventilated with an ambulatory bag. Using a 3mm flexible bronchoscope, the segmental bronchus is visualized and thehydrogel is ejected from the distal end of the catheter using a pusheror a guidewire. The suture attached to the hydrogel rod is used inconjunction with the guidewire to achieve accurate placement. Secretionspresent within the bronchial tree should enable the hydrogel to hydrateand expand. After a 10 minute period, the hydrogel should be firmlylodged within the bronchiole. The suture may now be detached and thebronchoscope withdrawn. When ventilation is resumed, after about 15minutes, the bronchus should be effectively occluded and no airleakshould be evident.

Example 13

Use of Hydrogel to Seal Cerebrospinal Fluid Leaks

Surgical treatment of tumors near the skull base generally entail atranssphenoidal approach, wherein surgery is performed through a nasalcavity. A common complication of this type of surgical procedure is acerebrospinal fluid leak due to rupture of the sellar floor. Persistentrhinorrhea may result, which is considered a major complication ofsurgery and may lead to life-threatening infections. Typically, at theend of such surgeries abdominal fat is harvested and used to plug thenasal cavity. There is therefore a need for a synthetic material thatcould be used for this purpose to obviate the surgical procedure toharvest the fat and reduce morbidity to the patient.

In accordance with the principles of the present invention, a hydrogelplug prepared as described in Example 6 may be introduced transnasallyand allowed to hydrate and effectively plug the nasal cavity, thuspreventing leakage of cerebrospinal fluid.

Example 14

Increased Rate of Hydration by Micropores

The process of freeze drying or lyophilization creates macro andmicropores within a dried hydrogel. These pores allow more rapid ingressof water and other aqueous fluids into the hydrogel, and cause the dryhydrogel to hydrate at a rate faster than that of an oven-driedhydrogel. The phenomenon may be illustrated by making two identicalhydrogels as described in Example 1. The first hydrogel is allowed todry in an oven at 50° C. overnight; the other hydrogel is frozen at −40°C. and then allowed to gradually freeze dry over a period of 1 day. Thehydrogels obtained then are allowed to rehydrate in physiologicalsaline. The normalized weights of the two hydrogels may be compared aswet weight/dry weight over a period of time. It is expected that themacroporous lyophilized dry hydrogel hydrates at a substantially fasterrate than the oven-dried hydrogel.

Example 15

Use of Osmolality Enhancing Agents to Speed Hydration

The driving force of aqueous fluid ingress in a hydrogel is primarilythe osmotic potential difference between the collapsed dried ornon-equilibrium hydrated hydrogel. Thus, the rate of fluid uptake ofhydration may be enhanced by incorporating osmolality enhancing agentsin the hydrogel.

A macromer solution is formulated as described in Example 1 and dividedinto two aliquots. In the first aliquot 200 mg/ml of NaCl is added;nothing is added further to the other aliquot. Rod shaped hydrogels areprepared from both formulations as described in Example 1. The hydrogelrods then are allowed to further hydrate by placing them in aphysiological salt solution, without first drying the rods. It isexpected that the hydrogel containing the NaCl will hydrate at asignificantly faster rate to its equilibrium level than the controlhydrogel.

Example 16

Use of a Wetting Agent or Consolute to Speed Hydration

In the experiment of Example 14, hydration of the lyophilized dryhydrogel is expected to be somewhat impeded by the presence of airbubbles present in the macro and micropores. PEG 600 may be added to themacromer solution described in Example 1 at a concentration of 5 mg/mland a hydrogel further formed and lyophilized as described in Example14. The lyophilized rod of dry hydrogel is expected to be more pliable.When the hydrogel rod is rehydrated in normal saline, it is expectedthat the hydrogel including the PEG 600 as a wetting agent willrehydrate somewhat faster than the rod of lyophilized hydrogel that didnot have any wetting agent incorporated.

Also, during the rehydration, it is expected that few air bubbles willbe observed in the hydrogel that contains the wetting agent. Themechanism for this increased rate of hydration is not readily apparentand may be due to the improved wetting characteristics of the hydrogel,the more expanded structure of the hydrogel in the water depleted form,or reduced interfacial tension between the water and the air presentwithin the micropores, thus allowing easy access to the interiorstructure of the hydrogel. That the mechanism is unknown, however, doesnot reflect on the utility of, or otherwise limit, the invention.

Modifications and variations of the present invention, the macromers andpolymeric compositions and methods of use thereof, will be apparent tothose skilled in the art from the foregoing detailed description. Whilepreferred illustrative embodiments of the invention are described above,it will be apparent to one skilled in the art that various changes andmodifications may be made therein without departing from the inventionand it is intended in the appended claims to cover all such changes andmodifications which fall within the true spirit and scope of theinvention.

1. A contraceptive method for blocking a lumen of a fallopian tube withan insertable-and-swellable hydrogel comprising: placing a hydrogel plugin a substantially deswollen state in a lumen of a fallopian tube;wherein the hydrogel changes from the substantially deswollen state toan expanded state to occlude the lumen; and wherein the hydrogel isremoved from the fallopian tube by biodegradation of the hydrogel. 2.The method of claim 1 wherein the hydrogel biodegrades spontaneously inthe lumen.
 3. The method of claim 2 wherein the spontaneous degradationis caused by hydrolysis.
 4. The method of claim 1 comprisingfreeze-drying the hydrogel to achieve the substantially deswollen state.5. The method of claim 1 wherein the hydrogel comprises poly(ethyleneglycol).
 6. The method of claim 1 wherein the hydrogel comprisesosmolality enhancing agents to accelerate a rate of hydration of thehydrogel.
 7. The method of claim 9, wherein at least a portion of thehydrogel is rod-shaped.
 8. The method of claim 9, wherein the hydrogelcomprises a radio-opaque contrast agent.
 9. The method of claim 9,wherein the hydrogel comprises an alginate-based gel cross-linked withcalcium.
 10. The method of claim 9, wherein the hydrogel has a tensilestrength of at least 10 kPa.
 11. The method of claim 9 wherein thehydrogel consists essentially of synthetic materials.